Method of Modulating Production of Secondary Metabolites

Abstract

The invention relates to a method of modulating production of a metabolite in an actinomycetes bacterium comprising increasing the expression or activity of the Sporulation and Antibiotic Production Related gene A (SarA. SCO4069) polypeptide to modulate production of the metabolite in the actinomycetes bacterium. In one embodiment, the metabolite is valinomycin, daidzein, fluvirucin, demethyllydicamycin, or TPU-0037 analogues A. C and D.

1 . A method of modulating production of a metabolite in an actinomycetes bacterium, the method comprising increasing the expression or activity of the Sporulation and Antibiotic Production Related gene A (SarA) polypeptide to modulate production of the metabolite in the actinomycetes bacterium. 
     
     
         2 . The method of  claim 1 , wherein the method increases or decreases the production of the metabolite in the actinomycetes bacterium. 
     
     
         3 . The method of  claim 1 , wherein the metabolite is a secondary metabolite. 
     
     
         4 . The method of  claim 1 , wherein the metabolite is valinomycin, daidzein, fluvirucin or demethyllydicamycin. 
     
     
         5 . The method of  claim 1 , wherein the metabolite is a compound having the formula of: 
       
         
           
           
               
               
           
         
         wherein R 1  is H or Me and wherein R 2  is H or OH. 
       
     
     
         6 . The method of  claim 1 , wherein the actinomycetes bacterium is a  Streptomyces  bacterium. 
     
     
         7 . The method of  claim 1 , wherein the method comprises genetically modifying the actinomycetes bacterium to have increased expression or activity of the SarA polypeptide. 
     
     
         8 . The method of  claim 1 , wherein the method comprises introducing an expression construct comprising a heterologous SarA gene that is operably linked to a promoter to the actinomycetes bacterium. 
     
     
         9 . The method of  claim 1 , wherein the method comprises culturing the actinomycetes bacterium so as to modulate the production of the metabolite in the actinomycetes bacterium. 
     
     
         10 . A method of screening for a metabolite produced by an actinomycetes bacterium, the method comprising a) increasing the expression or activity of the Sporulation and Antibiotic Production Related gene A (SarA) polypeptide in an actinomycetes bacterium to modulate production of the metabolite in the actinomycetes bacterium; and b) screening for production of the metabolite in the actinomycetes bacterium. 
     
     
         11 . The method of  claim 10 , wherein the method comprises introducing an expression construct comprising a heterologous SarA gene that is operably linked to a promoter. 
     
     
         12 . A method of preparing a drug compound library, the method comprising a) increasing the expression or activity of the Sporulation and Antibiotic Production Related gene A (SarA) polypeptide in an actinomycetes bacterium to modulate production of metabolites in the actinomycetes bacterium; and b) isolating metabolites from the actinomycetes bacterium to prepare the drug compound library. 
     
     
         13 - 15 . (canceled)